Abstract: The ability of an organism to thrive pits two fundamental processes against each other: the desire to maintain genomic integrity with the necessity to explore different genetic states in order to adapt to a changing environment. In this proposal, I suggest that the genomic context can influence the likelihood for genetic change at a given locus, providing a mechanism to ""target"" alterations to specific genes. Further, I suggest a model in which tethering of change-vulnerable loci to elements of the nuclear architecture restrains genetic change under supportive growth conditions, whereas stress releases such constraints, leading to an increase in genetic change. I propose to study genetic changes in loci encoding cell surface proteins in fission yeast as a model for antigenic variation employed by many pathogens. Primarily, we will utilize assays for intra- and intergenic recombination within and between copies of genes encoding adhesin family members. We will examine the effect of environmental stress on the probability of changes in the adhesin loci. Based on our preliminary data, we will pursue the hypothesis that adhesin loci are associated with the nuclear periphery, which we believe represses recombination. In addition to investigating how exposure to stress affects the nuclear position of adhesin loci, we will also identify the molecules that serve as nuclear envelope tethers. This model predicts that loss of these peripheral tethers will recapitulate the effects of stress on recombination, which we will test. Lastly, we will carry out genetic screens to reveal how stress triggers release of adhesin loci from the nuclear periphery. The ability to intervene during this signaling cascade would provide new avenues to combat the pathogenecity of a wide array of microbes. Public Health Relevance: In order to cope with an environmental insult, organisms respond by adaptive change. Although a substantial response can be achieved through regulation of the genome, pathogenic organisms utilize genetic change to increase the potential for expressing novel proteins that support virulence and allow them to evade the host immune system. The goal of this proposal is to discover how pathogens mobilize the adaptive response so that interventions might be devised to more effectively treat infection.